1-aroylindole-3-acetonitriles

ABSTRACT

1-Aroylindole-3-acetic acids are prepared via 1-aroylindole-3acetaldehydes and their acetals, or 1-aroylindole-3-ethanols and their ethers and esters, or 1-aroylindoxyls, or 1-aroylindole-3acetonitriles. The Fischer indole synthesis gives the acetals, ethers, esters or nitriles which are then aroylated in the 1position. Hydrolysis to aldehydes and alcohols permits oxidation to the acids. The nitriles are hydrolyzed enzymatically to the acids. The 1-aroylindoxyls, formed by ring closure of N-aroyl-No-carboxyphenyl alanines, are converted to the 1-aroylindole-3acetic acids via the malonic acid, Reformatsky, Grignard, or Wittig syntheses.

United States Patent 511 int. c|.... com 27/56 [50] Field of Search 260/326. 1 6

[5 6] References Cited UNITED STATES PATENTS 3,294,811 12/1966 Shen et al. 260/302 Primary Examiner Alex Mazel Assistant Examiner-J. A. Narcavage Attorneys-Harry E. Westlake, .lr., l. Louis Wolk and Michael C. Sudol, Jr.

ABSTRACT: l-Aroylindole-3-acetic acids are prepared via laroylindole-3-acetaldehydes and their acetals, or l-aroylindole-3-ethanols and their ethers and esters, or l-aroylindoxyls, or 1-aroylindole-3-acetonitriles. The Fischer indole synthesis gives the acetals, ethers, esters or nitriles which are then aroylated in the 1-position. Hydrolysis to aldehydes and alcohols permits oxidation to the acids. The nitriles are hydrolyzed enzymatically to the acids. The l-aroylindoxyls, formed by ring closure of N-aroyl-N-o-carboxyphenyl alanines, are converted to the l-aroylindole-Ii-acetic acids via the malonic acid, Reformatsky, Grignard, or Wittig syntheses.

l -AROYLINDOLE-3-ACETOES RELATED APPLICATIONS This application is a division of. application Ser. No. 616,496, filed Feb. 16, 1967, and now US. Pat. No. 3,470,203, which in turn is a continuation-in-part of our copending applications Ser. No. 255,642 filed Feb. 1, 1964, and Ser. No. 496,701 filed Oct. 15, 1965, both now abandoned.

BACKGROUND OF THE INVENTION The discovery by Shen (US. Pat. No. 3,161,654) that laroylindole-3-alkanoic acids are powerful anti-inflammatory drugs has brought forward practical difficulties in technical synthesis. In order to aroylate indole acetic acids, it was necessary to protect the acid function because the ring nitrogen must be treated with sodium hydride to form the N-metallo derivative. The ordinary protecting groups (e.g. esters) are removed by reagents which also tend to remove the l-aroyl group. It has therefore been necessary to use protecting groups which are removable by special reactions not affecting the l-aroyl, such as hydrogenation of benzyl esters, pyrolysis of t-butyl esters and the like. There is thus a need for intermediates which can be aroylated easily and then be converted to the acids.

SUMMARY OF INVENTION This invention relates to certain intermediates which can be readily converted to the free l-aroyl indolyl alkanoic acids after the aroylation of the l-position. Thus, the indolyl-3- acetaldehyde acetals and 3-ethanol ethers are readily prepared by the Fischer indole synthesis from phenylhydrazines and levulinaldehyde acetals or S-ketoalkanol ethers. These can then be aroylated in the 1-position by the standard method. Hydrolysis of the acetals gives the aldehydes and of the others give the free alcohols. Each can then be oxidized to the free acids. Similarly, the use of levulinonitrile gives the indole-3-acetonitriles which, after l-aroylation, are enzymatically hydrolyzed to the indole acids. By ring closing an N-aroyl-N-o-carboxyphenylalanine, there is obtained a 1- aroylindoxy which also is a key intermediate, since any of the Wittig, Grignard, Reformatsky or malonic acid syntheses can be used to convert it to a l-aroylindole-3-alkanoic acid. Each of these intermediates is thus a key to an easy attainment of these important drugs.

DESCRIPTION OF THE INVENTION This invention relates to novel intermediates for preparing a-( 3-indolyl) lower aliphatic acids having an aromatic carboxylic acyl (i.e., an aroyl or heteroaroyl) radical of less than three fused rings attached to the nitrogen atom of the indole ring. These N-l aroyl and N4 heteroaroyl indolyl aliphatic acid compounds, useful as anti-inflammatory drugs, may be chemically represented by the structural formula:

wherein R, is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl radicals; R, is selected from the group consisting of a hydrogen atom and lower alkyl, lower alkenyl, aryl, aralkyl, alkaryl, substituted alkyl and substituted aryl radicals;

R is selected from the group consisting of a hydrogen atom and lower alkyl and lower alkenyl radicals;

R is selected from the group consisting of hydroxy, Nl-l,, substituted Nl'l ,'amine salts, lower alkoxy, aralkoxy and --OM radicals, said M being a cation; and

R is selected from the group consisting of hydrogen and halogen atoms, and lower alkyl, lower alkoxy, halo-alkyl, nitro, amino, substituted amino, cyano, aminomethyl, alkyl-substituted aminomethyl, mercapto, dialkylsulfonamide and benzyl-mercapto radicals.

A critical feature of the above compounds is the presence of an aroyl or heteroaroyl radical attached to the N-l position of the indole nucleus. These acyl groups may be further substituted in the aromatic rings thereof with hydrocarbon groups or with functional substituents. The term functional substituent," as used herein, is meant one other than hydrogen or hydrocarbon.

Among the preferred aroyl substituents that are operable herein are the benzoyl and naphthoyl groups. The aromatic rings of such groups may contain, and in the preferred compounds do contain, at least one functional substituent. This substituent may be a hydroxy or an etherified hydroxy (hydrocarbonoxy) group such as a lower alkoxy, aryloxy or an aralkoxy radical, e.g., methoxy, ethoxy, isopropoxy, propoxy, allyloxy, phenoxy, benzyloxy, halobenzyloxy, lower alkoxybenzyloxy and the like. Said functional substituent may also be a nitro group, representative examples of which that might be mentioned are acylamino, amineoxide, ketimines, urethanes, lower alkylamino, lower dialkylamino, amidine, acylated amidines, hydrazine or a substituted hydrazine, alkoxyamines and sulfonated amines, Furthennore, said functional substituent may be a mercapto or a substituted mercapto radical of the type exemplified by alkylthio groups, such as methylthio, ethylthio, and propylthio and arylthio or aralkylthio groups, e.g., benzylthio and phenylthio. The N-l aroyl radical may, if desired, be haloalkylated, as with a trifluoromethyl, trifluoroethyl, perfluoroethyl, fi-chloroethyl or like substituent, acylated as with acetyl, propionyl, benzoyl, phenylacetyl, trifluoroacetyl and like acyl groups, or it may contain a haloalkoxy or haloalkylthio substituent. In addition, the invention embraces compounds wherein the aroyl radical contains a sulfamyl, benzylthiomethyl, cyano, sulfonamido or dialkylsulfonamido radical. Further, it may contain a carboxy substituent, or a derivative thereof, such as an alkali metal salt or a lower alkyl ester of the carboxy radical, an aldehyde, azide, amide, hydrazide and the like, or an aldehyde derivative of the type represented by acetals or thioacetals. In the preferred compounds, the N- l aroyl radical is benzoyl and the functional substituent is in the para position of the sixmembered ring.

In accordance with this invention, the N-l group may be a heteroacyl substituent in which the heterocyclic moiety is a five or six-membered heteroaromatic ring, preferably of less than three fused rings. Examples of such radicals are the furyl, thienyl, pyrryl, thiazolyl, thiadiazolyl, pyrazinyl, pyridyl, alkylpyridyl, pyrazolyl, imidazolyl, oxazolyl, pyrimidinyl and isoxazolyl rings. Said heteroaroyl radicals may be further substituted in the aromatic rings thereof with hydrocarbon groups or with functional substituents.

R situated in the 2-position of the indole ring nucleus, may be hydrogen, although it is preferred that there be present at this position of the molecule a hydrocarbon radical having less than nine carbon atoms. Lower alkyl groups such as methyl, ethyl, propyl or butyl are the most satisfactory although aryl, alkaryl and aralkyl groups are also advantageous, such as phenyl, benzyl and tolyl. Furthermore, the alkoxy, halo, amino, substituted amino and nitro substituted derivatives of the foregoing are within the purview of this invention as are indoles having at the 2-position an unsaturated aliphatic radical such as allyl or vinyl or a cylic aliphatic residue of the type cyclohexyl.

The acidic moiety of the active Nl acylated a-( 3-indolyl) aliphatic acids produced form the intermediates of this invention is preferably a lower aliphatic acid such as acetic, propionic, butyric, valeric, 3-butenoic, -pentenoic and the like acids. Accordingly, R in the foregoing formula may be a hydrogen atom, a lower alkyl radical such as methyl, ethyl, propyl and the like, or a lower alkenyl radical such as vinyl, allyl and the like.

in the preferred compounds of the invention, R is a lower alkyl, lower alkoxy, nitro, amino or substituted amino group. Examples of the alkyl and alkoxys that are embraced herein are methyl, ethyl, propyl, t-butyl, methoxy, ethoxy, i-propoxy and the like radicals. Examples of the substituted amines are those derived from alkyl amines such as methylamino, ethylamino, isopropylamino, butylamino, diethylarnino, ethylsec-butylamino, diiso-propylamino and the like, alkanolamines such as ethanolamino, diethanolamino, Z-aminol-butanol, morpholine and the like, aryl amines such as aniline, diphenylamine and the like, aryl amines such as aniline, diphenylamine and the like, mixed aromatic-aliphatic amines such as monomethylaniline, monoethylaniline and the like, aralkyl amines such as benzylamine, B-phenylethylamine and the like, halo-substituted aliphatic or aromatic amines such as fi-chloroethylamine; para-chloroaniline, parachlorobenzylamine and the like, and other substituted aliphatic or aromatic amines such as ,B-methoxyethylamine, para-tolylamine, para-methoxyaniline, and the like. R is not limited to the foregoing classes of substituents, however, and may, if desired, represent substituents such as hydrogen, aryl, aryloxy, hydroxy, mercapto, halo, haloalkyl such as CF CHF, and the like, nitro, haloalkyl, cyano, sulfamyl, sulfoxide, aminomethyl, substituted aminomethyl, carboxy and carboalkoxy groups.

The nitriles, aldehydes, acetals, alcohols and ethers of this invention are important intermediates in the synthesis of the corresponding indolyl-3-alkanoic acids and in many cases are themselves of importance as end products.

The synthesis of various compounds of this invention having on the indole ring system a S-substituent which has a nitrogen attached to the homocyclic ring of the indole is generally based on the S-nitro compound which may subsequently be transformed into the desired t-substituent. Such transforma tion can be carried out in a number of ways. Reduction of the S-nitro groups gives a S-amino group. Reaction of the amino with alkyl halides gives mono and dialkyl amine groups. If the alkyl halide is a dihalo-alkylene group (e.g., 1,4-dibromobutane) a heterocyclic ring (e.g., pyrrolidino) is formed. Similarly, bis()8-chlorethyl)ether will give an N-morpholine compound. Alkylation can also be carried out simultaneously with reduction, e.g., with formaldehyde and Raney nickel and hydrogen. Acylation' can similarly be carried out on the 5- amino compounds or on the S-nitro (with simultaneous reduction) to give S-acylamido compounds. The S-amino group can be reacted with iso-cyanates to give S-ureido compounds.

The a-[( l-aroylor l-heteroaroyl)-3-indolyl] aliphatic compounds of this invention are intermediates for the preparation of 3-indolyl alkanoic acids which have a high degree of anti-inflammatory activity and are effective in the prevention and inhibition of granuloma tissue formation. Cer rain of them possess this activity in high degree and are of value in the treatment of arthritic and dermatological disorders and in like conditions which are responsive to treatment with anti-inflammatory agents. In addition, the compounds of this invention have a useful degree of antipyretic activity. For these purposes, they are normally administered orally in tablets or capsules, the optimum dosage depending, of course, on the particular compound being used and the type and severity of infection being treated. Although the optimum quantities of these compounds of this invention to be used in such manner will depend on the compound employed and the particular type of disease condition treated, oral dose levels of preferred compounds in the range of 1.0-200 mg. per day are useful in control of arthritic conditions, depending on the activity of the specific compound and the reaction sensitivity of the patient. The compounds of this invention are primarily in- Ail termediates for the preparation of these pharmaceutically active indolyl acids but they also themselves, in some cases, possees the same biological activity.

The preparation of the intermediates of this invention and their use in preparing the indolyl acids are described below. For purposes of discussion, these routes are grouped below by the general feature of the intermediate described. Each intermediate or group of intermediates has an accompanying Flow Sheet illustrating the reactions used and bearing the corresponding number for convenience. For further convenience, each reaction in the Flow Sheets is numbered with a number which, as well as being a key to the list of reagents and conditions at the end of each Flow Sheet, corresponds to the Example illustrating the reaction involved.

Formation of Side Chain Carboxyl from Acetals, Esters and Ethers One method of synthesizing these compounds is to synthesize the entire indole molecule with either an aldehyde acetal or an alcohol ether or ester group in place of the carboxy function in the side chain. The latter is then hydrolyzed and oxidized into the carboxy.

The use of acetals is shown in A of Flow Sheet 1. Acetals of levulinaldchyde are used as one of the starting materials in the Fischer indole synthesis. The resulting indolyl-3-acetaldehyde derivative is then acylated easily in' the l-position. Hydrolysis of the l-acyl indolyl acetaldehyde acetal yields the corresponding aldehyde which is readily oxidized in acid solution (where the l-acyl group is stable) by strong oxidizing agents such as KMnO dichromates, peroxides, CrO, in acetic acid, oxygen over Pr0,, and the like, to yield the desired indolyl acetic acid products.

Both the aldehydes and the acetal precursors are embodiments of this invention, because of their importance in the synthesis of the anti-inflammatory indolyl acids. The acetals can be any alkyl (suchasmethyl, ethyl, propyl, butyl, t-butyl, octyl, lauryl or octadecyl), alkenyl (such as allyl, crotyl) aralkyl (such as benzyl and substituted benzyl) cyclic such as alkylene (ethylene, propylene) or cycloalkyl (such as cyclohexyl, cyclopentyl and the like). Preferably, it is lower alkyl. Levulinaldehyde acetals are well known in many cases and the same preparative methods are usable for any of these acetals. Preferably a lower alkyl acetal such as methyl, ethyl or butyl is used. The acetals and the aldehydes produced therefrom can also have biological activity of their own but they are especially useful as intermediates for the acids.

When an etherified S-keto-primary alcohol is used in the indole synthesis, a similarly advantageous synthesis is achieved and the intermediate ethers and alcohols are similarly embodiments of this invention. The etherifying group can be an alkyl, especially a lower alkyl, an alkenyl, cycloalkyl or aralkyl. Especially preferred as etherifying groups are those having a tertiary carbon bonded to the oxygen, since these decompose readily in acid solution on heating. Examples are t-butyl and trityl (triphenylmcthyl). Also preferred is benzyl, which can be removed by hydrogenation. Removal of protecting groups in the side chain is always a problem with the l-acyl group being sensitive to the usual treatments.

The ethers are also prepared by condensing a gamma chloro or bromo propyl ketone with the appropriate hydrazine in the indole synthesis. The resultant 3-chloro-ethyl indole is reacted with the appropriate alkali alcoholate to form the ether.

The esters of the S-keto alcohols can similarly be used as an intermediate in place of the ethers. The esterifying group can be any alkanoic acid (e.g., formyl, acetyl, propionyl, butyryl, stearyl, etc.) or an aromatic acid such as benzoic, thenoic, furoic, nicotinic and the like or an unsaturated acid such as crotonic, acrylic and the like. A lower alkanoic acid residue is preferred.

The esters can also be prepared from the alcohols by estherification with the appropriate acid chloride. This method may be convenient when these indolylcthyl esters are the products specifically desired for their biological activity. However, when the indolylacetic acids are desired, the esters are prepared by the Fischer lndole synthesis and the alcohol prepared from them after acylation. l-Acyiindoxyis as Intermediates Another method of preparing the i-aroyiindolyl-Zi-aikanoic acid compounds which forms a still further embodiment comprises the synthesis of 3-ketoindolines and the introduction, by means of the keto group, of the side chain into the heterocyclic ring. These 3-ketoindolines or indoxyls form a further embodiment of this invention.

This is accomplished by several routes as illustrated in Flow Sheet [1. A l-acyl-2,5-substituted 3-keto indoxyl can be synthesized as a key starting material (which is one of the embodiments of this invention) by several series of reactions, one of which is shown in How Sheet 11. Introduction of the side chain is accomplished by one of several well-known methods, namely the Reformatsky Reaction, the Wittig Reaction, m e i n an the sn s @FiQiEi/Mfiflti e te FLOW SHEET I Synthesis through scstals and ethers or acid syntheses. The keto is replaced with the desired ester side chain. When the ester used in any of these reactions is the tertiary butyl ester, the process of migrating the exo double bond in the case of the Wittig Reaction or of dehydrating the S-hydroxyl in the case of the Reformatsky Reaction or Grignard Reaction simultaneously pyrolyzes off the tertiary butyl group to form directly the compounds of Formula lX. If other esters are present, the esters of Formula Villa are formed instead and these are converted either by the methods indicated in the Flow Sheets to the indolyl acid compounds. In the case of the cyano acetic ester synthesis, the intermediate is not isolated but goes on to the 3-indolyl alkyl cyanide, another intermediate which is an embodiment of this invention, whose conversion to the corresponding esters and finally to the acid is described'in Flow Sheet ill. in the case of malonic esthers, one uses the t-butyl mixed ester and gets a 3-indolyi alkanoic acid ester directly. These esters are transformed to the acids by enzymatic hydrolysis or (when they are t-butyl esters) by pyrolysis.-

Synthesis Through the Nitrile Another alternative method of preparing the anti-inflammatory indolyl-3-acetic acid compounds in the reaction of a para substituted phenyl hydrazine with a levulino-nitrile to form a 2,5-substituted-3-indolyl alkyl nitrile. This can then be readily acylated in the l-position. The nitrile can then be converted methanol to give 10 percent methanol in the final 0.1-10 20 percent enzyme-nitrile substrate solution. Hydrolysis is carried out by stirring at room temperature, keeping the pH at 7-8.0 by the addition of alkali.

Because the the use of the nitrile permits acylation in the 1- position and conversion of the side chain into an acid side chain with great ease, avoiding the difficulties encountered when the acylation is carried out on an acid ester side chain and the ester must be removed without touching the l-acyl group, these 3-cyano methyl indoles 'are important inter- Equivalents:

R R R, and R, as defined in specifications R,=alkyl, alkenyl, aralkyl, cycloalltyl, substituted alkyl,

preferably lower alkyl.

R,,=alkyl, aralkyl, especially t-butyl, benzyl and trityl.

'1. Reflux under nitrogen in an inert solvent such as t-butanol.

2. Heating in an inert solvent with NaH, followed by cooling below room temperature and addition of an acid halide of R COOH.

3. Hydrolysis in dilute acid at room temperature.

40. Oxidation by Ag,O in an inert solvent such as benzene.

4b. Oxidation by oxygen over PtO, in anhydrous solvent such as dioxane.

5. Heating in t-butanol or other solvent under inert atmosphere.

6. Heating in inert atmosphere in t-butanol or other solvent.

7. Heating with an alkali alcoholate, using excess alcohol as the solvent.

8. Heating in inert solvent such as benzene with NaH, followed by low temperature addition of an acid halide of R,COOH.

9. Hydrogenation of benzyl ether or trityl ether in inert solvent such as ethylacetate in presence catalyst such as Pd on C.

10. Treatment of t-butyl ether with a strong anhydrous acid in the cold (e.g. CF,COOH at 10 C.).

ll. Treatment of trityl ether with dry HCl in inert solvent (cyclohexane) in the cold.

mediates and, as such, an additional embodiment of this in- 12. Oxidation with CrO, in acetic acid at low temperature vention. l0-25 C.

FLOW SHEET II Synthesis through indoxyl m- -c 0 0a (13) R!- --0 00a NH: NH-C R5 O-C OCH: 15 Rr- COOH c 0 OH -R NCH N I l COR R, C 0 R1 6) Ram 0 N B A 0 R1 7)/ 8) l v OH Ra OH Ill: R5 CHCOOH RF- CH-COOR; R; C-COOR;

H R2 R,

N N H f H 0 R1 (E 0 R] C 0 R1 (13 Reaction with an a-halo acid X R2( JH-C OOH in the presence of an acid binder such as a carbonate.

(14) Acylation by an acid v halide of R COOH in an organic base'such as pyridine.

t{15) Acetic anhydride and R CH COH at re ux.

(16) Refluxing with aqueous dioxane solution of sulfite (e.g. Na SO 17) Heating with a malonic acid in an organic base (e.g. pyridine) followed by heating the intermediate XLII in an inert solvent with a strong acid.

(1118) Reformatsky Reaction with an a-halo ester suc as C O O Ry Br-O\ using zinc catalyst at elevated temperatures in an inert solvent (e.g. refluxing in a. benzene-ether mixture). (19) Heating to 100 in an inert solvent (e.g. toluene) with a small amount of strong acid (e.g. p-toluene sulfonic acid).

(20) Wittig reaction with /Rs |Hi)a G 000R, by heating in an inert solvent such as CH Qh 21. Heating to 100 in an inert solvent (e.g., toluene) with a strong acid e.g., p-toluene sulfonic acid).

22. Grignard reaction with Cl-Mg-CH-COOR, in inert solvent (e.g., petroleum ether) followed by addition of cold NH Cl solutions.

v23. Retluxing with cyanoacetic acid or malonic acid in an inert solvent followed by dry HCl and anhydrous R,OH.

9 'mcneoon 23 R, f 0 0R,

Ili OH x R, in CH-CN (23) R t z-coomm I -R: i \N H 00R, 0R|

(SEE FLOW SHEET 111 Reagents: Equivalents:

R 11,, R, and R, as defined in specifications HX in LXXVII shows mineral acid salt (e.g., CHI).

Reagents: I

24. Alcoholic solution at elevated temperature (steam bath).

25. Heat with NaH in an inert solvent (e.g., toluene), then cool below room temperature and add an acid halide o RCOOH.

26. Microbiological hydrolysis with nitrilase as catalyst.

EXAMPLE 1 A mixture of 16.8 g. of the dimethylacetal of levulinaldehyde, 17.4 g. of p-methoxyphenyl hydrazine HCl and 120 ml. of t-butanol is heated at reflux under nitrogen for 5 hours. The product is precipitated by the addition of 120 ml. of water followed by cooling to 0- The product is filtered, washed 5 with 20 ml. of 50 percent aqueous t-butanol and ml. of water. Vacuum drying at -50 gives 19.1 g. (80 percent) of 2methyl-5-methoxy indolyl acetaldehyde dimethylacetal.

EXAMPLE 2 To a slurry of 5.5 g. of percent sodium hydride emulsion in 160 ml. of dry benzene is added 19.! g. of Z-methyl-S- methoxyindolylacetaldehyde dimethyl acetal. The mixture is heated at 80 over a period of 30 minutes. Afler the evolution 45 of hydrogen is complete the mixture is cooled to 8 and 16.8 g. of p chlorobenzoyl chloride is added, over a period of 30 minutesat 8-l2. After aging at 10 for 1 hour, 7.2 ml. of acetic acid is added dropwise at 10 over a period of 30 minutes. Sodium chloride is removed by filtration and the 50 benzene solution is concentrated to a small volume. Addition of petroleum ether precipitates the product which is filtered, washed with benzene-petroleum ether, and petroleum-ether. Vacuum drying at 45 gives 22.6 g. of l-p-chlorobenzoyl-Z- methyl-S-methoxyindolyl acetaldehyde dimethylacetal.

Similarly, when the diethyl, dibutyl, diallyl or dibenzyl acetals of levulinaldehyde are used in equivalent quantities in the procedure of example 1 and the product is acylated by the procedure of this example, the corresponding indolyl acetaldehyde acetals are prepared.

Similarly, when the appropriately substituted phenyl hydrazines and gamma keto aldehyde dimethyl acetals are used in the procedure in example 1 and the appropriate acid chloride or p-nitrophenyl ester is used to acylate the intermediate indole, there is obtained the dimethyl acetals of the followingaldehydes:

a-( 1-p-methylthiobenzoyl-Z-methyl-5-methoxy-3-indolyl)propionaldehyde;

a-( l-o-methyl-p-methylthiobenzoyl-2-methyl-5-methoxy-3- indolyl)propionaldehyde;

a-( l-benzoyl-2-methyl-5-methoxy-3-indolyl)propionaldehyde; l'ben20yl-2-methyl-5-methoxy-3-indolyl acetaldehyde; a-( l-p-fluorobenzoyl-2-methyl-5-methoxy-3-indolyl)propionaldehyde;

acetaldehyde; 1-(p-difluoromethoxybenzoyl)-2-methyl-5-methoxy-3-indoly1 acetaldehyde;

. a-(l-p-chlorobenzoyl)-2-methyl-5-ethoxy-3-indolyl l 1-p-benzyloxybenzoy1)-2-methyl-5-methoxy-3-indolyl acetaldehyde;

l 1 -p-hydroxybenzoyl)-2methyl-5-methoxy-3-indolyl acetaldehyde; l-(1-o-fluorobenzoyl)-2methyl-5-methoxy-3-indolyl acetaldehyde;

1-(fi-naphthoyl) Z-methyl-S-methoxy-Il-indolyl V acetaldehyde;

1-(5-chlorobenzoyl)-2-methy1-5-methoxy-3-indo1yl acetaldehyde; l-(5-chloro-2-thenoyl)-2-methyl-5-methoxy-S-indolyl acetaldehyde;

l-( l-p-trifluoromethy1benzoy1)-2-methyl-5-methoxy-3-indolyl acetaldehyde;

1-( o-p-diehlorobenzoyl)-2-methyl-5-methoxy-3-indolyl acetaldehyde;

a-( 1-p-chlorobenzoyl)-2-methyl-5-p-dirnethylsulfonamido-3- indolyl propionaldehyde;

a-( l-p-chlorobenzoyl )-2-methyl-5-benzylmercapto-3-indoly1 propionaldehyde; a-(1-p-chlorobenzoyl)-2-methyl-5-vinyl-I l-indolyl propionaldehyde.

EXAMPLE 3 l -p-Chlorobenzoyl-2-methyl-5-methoxy-3-indolyl acetaldehyde Crude l-p-chlorobenzoyl-2-methyl-5-methoxyindole-3- acetaldehydediethylacetal (3.0 g.) is stirred with 60 ml. of water-alcohol (1:1 and 3 ml. of concentrated hydrochloric acid for 4 hours at 25 C. to obtain the corresponding free aldehyde which is isolated by dilution with 300 ml. of water and ether extraction. After removal of the solvent, the product remains in the residue.

When any of the other aldehyde acetals shown in example 2 are similarly treated, the corresponding free aldehydes are obtained.

EXAMPLE 4 a. To a solution of 2.82 g. of l-p-chlorobenzoyl-Z-methyl-S- methoxyindole-B-acetaldehyde in ml. benzene, 2.4 g. of silver oxide is added portionwise, maintaining the temperature at 35 to 40 C. by external cooling. After 3 hours aging period, the silver salt of l-p-chloro-benzoyl-Z-methyl-S- methoxyindole-3-acetic acid is filtered and dried in vacuo. The free acid is liberated from the aqueous soiution of the silver salt by addition of acidic acid. The crude product is purifled by crystallization from t-butanol and found to be identical with standard sample of l-p-chlorobenzoyl-2-methyl-5- methoxyindole-ll-acetic acid.

b. To a solution of 2.82 g. of 1-p chlorobenzoyl-2-methyl-5- methoxyindole-3-acetaldehyde in 5 ml. of anhydrous dioxan, 0.5 g. hydrogenated platinum-on-charcoal is added. The mixture is heated to 40 C. and shaken in oxygen atmosphere until the theoretical amount of oxygen is absolved (approximately 2 hours). After the filtration the catalyst is removed in vacuo and the residue recrystallized from t-butanol.

The product has a melting point of 165 C. and shows no depression with sample of 1-p-chlorobenzoyl2-methyl-5- methoxyindole-Zi-acetic acid. The LR. and U.V. spectrums are identical with standard sample.

EXAMPLE 5 a. A mixture of 17.4 g. of p-methoxyphenylhydrazine HCl, 39 g. of the trityl ether of 4-keto pentanol and ml. of t-butanol is heated at reflux under nitrogen for 5 hours. Addition of 120 ml. of water and cooling to 0- precipitates the product which is filtered, washed with 20 ml. of 50 percent aqueous t-butanol and 35 ml. of water. Vacuum drying at 45 gives 32.6 g. of the trityl Z-methyl-S-methoxyindolyl-3-ethyl ether.

b. A mixture of 19.2 g. of benzyl ether of 4-keto pentanol, 17.4 g. of p-methoxyphenylhydrazine HCl and 120 m1. of t-butanol is heated at reflux under nitrogen for 5 hours. Addition of 120 ml. of water and cooling precipitates the benzyl indolyl ethyl ether which is filtered, washed with 20 ml. of 50 percent aqueous t-butanol and 35 ml. of water. Vacuum drying at 50 gives 25 g. of the benzyl ether of Z-methyI-S-methoxyindolyl #11 19 1... V i.

EXAMPLE 6 A mixture of 17.4 g. of p-methoxyphenylhydrazine l-lCl, 12 g. of 1-chloropentanone-4, 250 ml. of absolute ethanol and 13 ml. of 7.8N ethanolic hydrogen chloride is heated at reflux for 30 minutes. The mixture is concentrated to 75 ml. and the 2- methyl-S-methoxy-3-chlorethyl-indole is crystallized by the addition of 75 ml. of water. Yield: 14.5 g.

EXAMPLE 7 Sodium (1.5 g.) is reacted with 20 g. of benzyl-alcohol is ml. of benzene and 11.1 g. of 2-methyl-5-methoxy-3- chlorethylindole from example 6 is added. The mixture is heated at reflux for 1 hour, washed with water an concentrated to small volume. Addition of petroleum ether precipitates the product.

EXAMPLE 8 a. To a slurry of 5.2 g. of 50 percent sodium hydride emulsion in 150 ml. of dry benzene is added 32 g. of the trityl indole ether prepared in example 5a. The mixture is heated to 80 over a period of 30 minutes and held at 80 until no more hydrogen is evolved. The mixture is cooled to 8 and 15.7 g. of p-chlorobenzoyl chloride is added at 8-l0 in 30 minutes. After aging at 8"10 for 1 hour, 6.7 ml. of acetic acid is added dropwlse over a period of 20 minutes at 10 The sodium chloride formed is removed by filtration and the product is crystallized by concentration to a small volume and the addition of hexane. The trityl 1-p-chlorobenzoyl-2-methyl-5- methoxyindolyl-3-ethyl ether so produced is filtered, washed with hexane and dried at 50 in vacuum. Yield: 35 g.

b. To a slurry of 5.5 g. of 50 percent sodium hydride emulsion in m1. of dry benzene is added 23.6 g. of dry benzene, 23.6 g. of the benzyl indolyl ethyl ether produced in example 5b. The mixture is heated to reflux over a period of 30 minutes and held at reflux until no hydrogen evolution is noted. After cooling the mixture to 8, 16.8 g. of p-chlorobenzoylchloride is added dropwise over a period of 30 minutes at 8-12. The slurry is aged at 810 for 1 hour and the 7.2 m1. of acetic acid B-[ l-(isonicotinoyl)-2-methyl-5-methoxy-3-indolyl] ethanol; 3

B-[ l-( 3-chloroisonicotinoyl)-2-methyl-5-methoxy-3-indolyl] ethanol;

,B-[ l-( o-methoxynicotinoyl)-2-methyl-5-methoxy3-indolyl] ethanol; B-[ l-( o-phenylnicotinoyl)-2-methyl-5-methoxy-3-indolyl] ethanol; /3-[ l-(c-pyrone-S-carboxy )-2-methyl-5-methoxy-3 -indolyl] ethanol; B-[ l-(pyridazine-4-carboxy)-2-methyl-5-methoxy-3-indolyl] ethanol; B-I l-(3-keto-4-methyl-2-phenyl-2,3-dihydropyridazine-o-carboxy )-Z-methyl-S-methoxy-3-indolyl] ethanol; }3-[ l-(cinnoline-4-carboxy)-2-methyl-5-methoxy-3-indolyl] ethanol; B-[ l-( 2-methylmercapto-4-chloropyrimidine-5-carboxy)-2- methyl-5-methoxy-3-indolyll ethanol; B-[ l-( 2,4-dichloropyrimidine-5-carboxy)-2-methyl-5- rnethoxy-3-indolyl] ethanol; /3-[1-(pyrazinoyl)-2-methyl-5-methoxy-3-indolyl] ethanol; B-[ 1-( 5-methoxypyrazinoyl)-2-methyl-5-methoxy-3-indolyl] ethanol; B-[ 1-( p-difluoromethoxybenzoyl)-2-methyl-5-methoxy-3-indolyl] ethanol; B-[( l-p-chlorobenzoyl)-2-methyl-5-ethoxy-3-indolyl] propanol; ,B-[( l-pchlorobenzoyl)-2-methyl-5-butoxy-3-indolyl] propanol; B-[( l-p-chlorobenzoyl)-2-methyl-5-ethyl-3-indolyl] propanol; B-[( 1-p-chlorobenzoyl)-2-methyl-5-butyl-3-indolyl1 propanol; 1 B-[( l-p-chlorobenzoyl)-2-methyl-5-fluoro-3-indolyl] propanol; B-[ l-( l-p-bromobenzoyl)-2-methyl-5-methoxy-3-indolyl] ethanol; B-[ l-( 1-p-phenylbenzoyl)-2-methyl-5-methoxy-3-indolyl] ethanol; B-[ l-( l-p-acetoxybenzoyl)-Z-methyl-S-methoxy-3-indolyl] ethanol; B-[ l-( l,4-thiazolylcarboxy)-2-methyl-5-methoxy-3-indolyl] ethanol; B-[ l-( l,Z-thenoyl)-2-methyl-5 methoxy-3-indolyl] ethanol; B-[ l-( l-a-naphthoyl)-2-methyl-5-methoxy-3-indolyl] ethanol; 7 3-[ l-( l-p-benzyloxybenzoyl)-2-methyl-5-methoxy-3-indolyl] ethanol; B-[ l-( l-phydroxybenzoyl)-2-methyl-5-methoxy-3-indolyl] ethanol; B-[ l-( l-o-fluorobenzoyl)-2-methyl-5-methoxy-3-indolyl] ethanol; B-[ l-( l-a-naphthoylbenzoyl)-2-methyl-5-methoxy-3indolyl] ethanol; B-[ l-( l,S-chlorobenzoyl)-2-methyl-5-methoxy-3-indolyl1 ethanol; B-[ l-( l ,S-chloro-Z-thenoylbenzoyl)2-methyl-5-methoxy-3- indolyl] ethanol; B-[ l-( l-p-trifluoromethylbenzoyl)-2-methyl-5-methoxy-3-indolyl] ethanol; B-[ l-( l-o-p-dichlorobenzoyl)-2-methyl-5-methoxy-3-indolyl] ethanol; fi-[( l-p-chlorobenzoyl)-2-methyl 5-p-dimethylsulfonamido- 3-indolyl] propanol; B-I l-p-chlorobenzoyl)-2-methyl-5-benzylmercapto-3-indolyl] propanol; B-[ l-p-chlorobenzoyl)-2-methyl-5-vinyl-3-indolyl] propanol.

EXAMPLE. 9

a. A solution of 2.0 g. of 1-p-chlorobenzoyl-2-methyl-5- methoxyindole-3-ethanol benzyl ether in 50 m1. ethylacetate is hydrogenated in the presence of 0.4 g. palladium/charcoal catalyst under one atmosphere of hydrogen. The theoretical amount of hydrogen is taken up (0.5 hour) and after removal the catalyst is evaporated in vacuo. The residue is recrystallized from isopropanol. The product has an infra-red spectrum identical with l-p-chlorobenzoyl-2-methyl-S-methoxyindole- 3-ethanol.

b. A mixture of 5.0 g. of l-p-chlorobenzoyl-Z-methyl-S- methoxyindole-Ii-ethanol trityl ether and 1.0 g. of palladium/charcoal catalyst is shaken at room temperature with hydrogen under slightly more than atmospheric pressure. After the calculated amount of hydrogen is absorbed (3 hours), the catalyst is filtered off and the solvent is removed in vacuo. The residue is crystallized from isopropanol. The product is identical with standard samples of 1-15- chlorobenzoyl-Z-methyl-5-methoxyindole-3-ethanol.

EXAMPLE 10 A solution of 2.0 g. of l-p-chlorobenzoyl-Z-methyl-S- methoxyindole?3-ethanol-t-butyl ether, prepared by using the t-butyl ether of 4-ketopentanol in the procedure of example 5 or sodium t-butoxide in the procedure of example 7, in 8 ml. of anhydrous trifluoracetic acid is allowed to stand for 1 hour at 10 C. The solution is poured into 30 ml. of ice cold water and the mixture is extracted with chloroform. The chloroform extracts are washed with water, saturated sodium bicarbonate solution and finally with water. Afier drying over Na SO the solvent is removed in vacuo and the residue recrystallized from isopropanol. The product has an infra-red spectrum identical with l-p-chlorobenzoyl-2methyl-5-methoxyindole- Himse f...

EXAMPLE ll water. Afier 3 hours standing at 25 C., 250 ml. of chloroform is added to the reaction mixture. The solution is washed with water, saturated sodium bicarbonate solution and water, dried over Na,SO and the solvent is distilled of! in vacuo. The

residue is taken up in 100 ml. of warm petroleum ether. Upon cooling to 10 C. the crystallized butanol is separated by filtration. Petroleum ether is removed in vacuo and the residue crystallized from bopropanol. This product has an infra-red spectrum identical with l-pchlorobenzoyl-Z-methyl-S- methoxyindole-3-ethanol.

EXAMPLEIZ To a stirred solution of 28.4 g. of l-p-chlorobenzoyl-Z- methyl-S-methoxyindole-B-ethanol in 100 ml. of acetic acid is added ml. of chromic acid solution (made by dissolving 20.1 g. of chromic acid in 20 ml. of water and diluted to 80 ml. with acetic acid) during 1.5 hours at 5 C. After standing overnight at room temperature, 300 ml. of water is added and the precipitated solid is filtered off and purified by crystallization from S-butanol. This product has an infra-red spectrum identical to l-p-chlorobenzoyl-2-methyl-5-methoxyindole-3 acetic acid.

EXAMPLE 13 A mixture of 16.7 g. (0.1 mole) of S-methoxy anthranilic acid, 11.9 g. (0.11 mole) a-chloropropionic acid, 45.6 g. (0.43) sodium carbonate and 75 ml. water is stirred under reflux for 12 hours. After addition of another 11.9 g. a chloropropionic acid and 20 ml. water, reaction is resumed for another 12 hours. After cooling, the product is precipitated with hydrochloric acid (50 ml.) and recrystallized from aqueous acetic acid. It is N-( 2-carboxy-4-methoxyphenyl)alanine.

EXAMPLE 14 To l50 ml. pyridine and 31.8 g. are added, with stirring and cooling, first 35 g. (0.2 mole) parachlorobenzoyl chloride, and then 23.9 g. (0.1) N-(2-carboxy-4-methoxyphenyl)alanine.

and acetaldehyde acetals.

The mixture is heated 4 hours on the steam bath and, after distillation of most of the pyridine in vacuo, it is cooled, diluted slowly with 500 ml. water, and acidified with HCI. The product is extracted into chloroform and after drying (Mg- SO.) and removal of most of the solvent, N-p-chlorobenzoyl- N-(2-carboxy-4-methoxyphenyl)alanine crystallizes on cooling to 5. 1

EXAMPLE 1s A mixture of 37.8 g. N-parachlorobenzoyl-N-(2-carboxy-4- methoxyphenyl)alanine (0.1 mole), 24.6 g. (0.3) sodium acetate and 125 ml. acetic anhydride is stirred and refluxed one hour, cooled to 75 and slowly diluted with 25 ml. water. Solvents are largely removed in vacuo and the acetate precipitated by adding to 250 ml. water.

EXAMPLE 16 a. The product of example 15 is converted to the indoxyl by refluxing overnight with 200 ml. water, 125 ml. dioxane and 20 g. sodium .sulfite. After concentration in vacuum and dilution with water, the product, 1-p-chlorobenzoyl-2-methyl-5- methoxyindoxyl, is filtered and recrystallized from ethanol.

b. When the appropriate acid chloride is used in example 14 in place of p-chlorobenzoyl chlorideand the product is carried through examples 15 and 160, there is obtained a 1-acy1-2- methyl-S-methoxyindoxyl in which the l-acyl group is any of the l-acyl groups on the ethers of example 8 or the acetals of example 2.

Similarly, when the appropriate N-(4-substituted-2-carboxyphenyDalanines are used in place of the 4-methoxy compound in the procedure of example 14 and the product Similarly, when the appropriate N-(4 s ubstituted-2-carbox yphenyl)alanines are used in place of the 4-methoxy compound in the procedure of example 14 and the product is carried through the procedures of examples l5 and 160, the product obtained is a l-acyl indoxyl having the other 5-substituents shown in examples 2 and 8 on indolyl ethanol ethers EXAMPLE 17 Ten and four-tenths grams of malonic acid, 29.9 g. of l-pchlorobenzoyl-Z-methyl-S-methoxyindoxyl and 25 ml. of pyridine are mixed and warmed to 40 C. till the acid is dissolved. Piperidine (0.8 ml.) is then added and the temperature of the reaction mixture raised to 80 C. for 3 hours. The cooled reaction mixture is poured into 200 ml. of cold water and acidified with 5N hydrochloric acid to pH 2 to 2.5. The crystals are collected, washed with water. The washed acid (30.5 g.) is dissolved in 200 ml. of benzene, containing 2.5 g. p-toluenesulfonic acid and heated to reflux. The water which is formed is separated by a Dean-Stark separator.

After no water formation is observed (2 hours) the hot benzene solution is washed three times with hot (75 C.) water, dried and concentrated to 100 ml. and cooled to 10. The crystalline product is filtered and recrystallized from t-butanol. M.P., 158-150 C.

EXAMPLE 18 A mixture of 31.6 g. N-parachloroberizoyl-Z-methyl-S- methoxyindoxyl (0.1 mole) and 500 ml. of 1:1 benzene-ether is refluxed with stirring for 5 hours, during which time 23.5 ml. of t-butyl bromoacetate is added, and, in portions accompanied by small iodine crystals, 50 g. of granular zinc. After two hours more of reflux, the reaction is cooled, 50 ml. of 1:1 methanol-acetic acid is slowly added, and the zinc filtered and washed several times with ether. The combined solutions are shaken with 400 ml. water and 20 ml. acetic acid. The layer is washed three times with dilute ammonia (100 ml.) and once with water 100 ml.) after drying (MgS and removal of the solvents to yield crude 1-p-chlorobenzoyl-2-methyl-3-hydroxy--methoxyindole-3-acetic acid S-butyl ester.

EXAMPLE 20 a. Preparation of Ylid Toa solution of 262 g. triphenylphosphine in 1,200 ml. benzene, add over 30 minutes, 183 g. t-butyl bromoacetate at 35-40. Stir overnight, filter and wash with benzene-pentane, dry at 40 in vacuo. The phosphonium salt is converted to the ylid by stirring in cold water (50 g./Iiter) and neutralizing to phenolphthalein with dilute alkali. The product is filtered, washed, dried, and recrystallized from pentene-acetic acid.

b. Wittig Reaction To 37.6 g. 0.1 ylid in C1'l,(3l (50 ml. slowly add a concentrated solution of 31.6 g. (0.1) indoxyl in the same solvent. Reflux overnight, concentrate to half volume, add 100 ml. petroleum-ether and filter the b,P=0 quickly while still warm. Chill in ice to precipitate the product. A second crop can be obtained by concentrating the mother liquors.

EXAMPLE 21 EXAMPLE 22 31.57 g. (0.1 mole) of l-p-chlorobenzoyl-Z-methyl-S- methoxyindolyl is added to a slurry of 0.11 mole of chloromagnesium-t-butylacetate in 300 ml. of petroleum ether (prepared from isopropylmagnesium chloride and tbutyl-acetate). The slurry is aged at 20-60 C. for l to 5 hours with good stirring. The hydroxy ester is obtained by addition of 200 m1. 20 percent ice cold ammonium chloride solution to the reaction mixture. The precipitated product is isolated by filtration and dried in vacuo.

The crude hydroxy ester is added to a solution of 3.0 g. of ptoluene sulfonic acid in 300 ml. of toluene. The solution is heated to reflux. The water formed during the reaction is separated continuously by means of Dean-Stark isobutylene formation (1,950 ml.) is observed. After the reaction is completed (2 hours), the toluene solution is cooled to C. and washed three times with warm (7580 C.) water to remove p-toluene sulfonic acid. The toluene solution is dried-while hot-over M380 and concentrated to ml. in vacuo. After the mixture is cooled, the crystalline product is filtered and recrystallized from boiling t-butanol. The dried product melts at 158-159 and it is identical in every aspect with 1-p-chlorobenzoyl-2-methyl-5-methoxyindole-3-acetic acid.

EXAMPLE 23 A mixture of 157.8 g. of lp-chlorobenzoyl-2-methyl-5- methoxyindolyl, 42.5 g. of cyanoacetic acid, 1.5 g. ammonium acetate, 6 ml. acetic acid, and 50 ml. benzene is refluxed with stirring for 24 hours, using a Dean-Stark trap to remove the water formed. After cooling, the reaction mixture is diluted with ml. benzene, washed several times with water, dried, and evaporated to a small volume. On chilling, the intermediate 1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl acetonitrile separates and is obtained by filtration.

When any of the other indoxyls prepared as shown in example 16b is used in the above procedure, the corresponding indolyl acetonitrile is obtained.

A solution of 25 g. of p-methoxyphenyl hydrazine hydrochloride and 20 g. of levulinonitrile in 250 ml. of 2N ethanolic HC] is heated on a steam bath for a few minutes. An exothermic reaction ensues, with Ni-LC] separating. The mixture is allowed to reflux gently without heating until the exothermic reaction subsides. It is then heated at reflux for 30 minutes and concentrated in vacuo to about 80 ml. Dilution with 400 ml. of water is followed by ether extraction. The extract is washed with saturated NaHCO; solution followed by i water and dried. The dry solution is filtered and concentrated to a dark syrup which is purified by chromatography on acid washed alumina, eluting with ether-petroleum ether mixtures progressing from 1:9 to 1:1. The syrup so obtained is crude 2- methyl-5-methoxyindole-3-acetonitrile.

EXAMPLE 25 The procedure of example 2 is followed, using 2-methyl-5- methoxy-S-indolyl acetonitrile as the starting material instead of the product of example 1, to produce l-p-chlorobenzoyl-2- methyl-S-methoxy-S-indolyl acetonitrile.

EXAMPLE 26 The nitrilase enzyme used is extracted with 0.1 M phosphate buffer, pH 7.5, from the leaves of oats (Avena), barley (Hondeum), the Brassica-family and certain Musaceoe. Ten (l0) to 50 g. of the material are extracted per 100 ml. of buffer.

l-p Chiorobenzoyl-2methyl-5-methoxy-3-indolyl acetonitrile is dissolved in a quantity of methanol such that the finalconcentration of methanol is between to 30 percent in the enzyme-substrate mixture. The final substrate concentramm is es b t een 9- 9;192mm: hshxqrqivsisisss e ried out at 25 37 C. for l to 6 hours. The pH is maintained at 7.0-8.0 bythe addition of dilute alkali'At end of this time, the mixture is acidified to pH 1-2 with dilute HCl and extracted with chloroform. The chloroform extracts are washedwith water and concentrated in vacuo to dryness leaving a residue of crude indornethacin.

EXAMPLE 27 a. The procedure of example 50 is followed, using the acetate ester of 4-ketopentanol in equivalent quantity in place of the trityl ether of the same alcohol. The product obtained is 2-methyl-5-methoxyindolyl-3-ethyl acetate.

b. The procedure of example 8a is followed, using the product of example 270 in place of that of 5a. The product obtained is l-p-chlorobenzoyl-2-methyl-S-methoxy-indolyl-Iiethyl acetate.

c. The procedure of example ll is followed, using the product of example 27b in place of the trityl ether. The product obtained is l-p-chlorobenzoyl-2-methyl-5-methoxyindolyl-3-ethanol.

EXAMPLE 28 acid ' p-acetarninobenzoyl chloride;

o-tluoro-p-chlorobenzoyl chloride; o-methoxy-p-chlorobenzoyl chloride; o-hydroxy-p-chlorobenzoyl chloride; 2,4,5-trichlorobenzoy] chloride.

EXAMPLE 29 the above procedure, the following esters are prepared:

B-[ l-( 5-nitro-2-furoyl)-2-et.hyl-5-fluoroindole-31 propyl propionate;

B-[( 1-nicotinoyl)-2-phenyl-5-bcnzyloxyindole-3] butyl benzoate;

' pr 1-( l-methylbenzimidazoi-2-carboxy)-2-cyclohexyl-4- trifluoromethyl-5-diisopropylsulfamylindole-31-pisopropylethyl butyrate;

B-[ l-(thiazole-4-carboxy)-2-isopropyl-5-nitroindole-3 l-hexyl phenylacetate;

,8-[ l-(p-Phen0xybenzoyl)-2-butyl-5-benzylthioindole-3] pentyl nicotinate;

B-[ 1-(2-phenylthiazole-4-carb0xy)-2-(o-tolyl)-S-phenyloxyindole-3] ethyl-Z-pyrrolecarboxylate;

B-[ l-( p-methylsulfonylbenzoyl-Z-cyclopentyl-5-benzyloxyindole-3] pentyl cyclopropylacetate;

B-[ l-( p-benzylthiobenmyl-Z-ethyl-S -chloromethylindole-3] ethyI-Z-benzimidazole carboxylate;

B-[ l-(2,4,5-trichlorobenzoyl)-2-benzyl-5-cyclopropylindole- 3 1-13-t-butyl-ethyl crotonate;

B-[ l 3,4,5-trimethoxybenzoyl )-2-methyl-5-cyclobutylmethoxyindole-3] butyl-2-ethoxy propionate.

EXAMPLE 30 B-[ l-( p-chlorobenzoyl)-2-methyl-5-nitro-3-indolyl] ethanol (0.! mole), 0.1 mole of finely powdered phthalic anhydride and m1. of benzene are heated together at C., with frequent stirring, for 8 hours. The precipitate is filtered, dissolved in dilute sodium carbonate and shaken with ether. The aqueous solution, free of ether, is then acidified and the crude mono acid separates. It is taken up in chloroform, washed with 23 24 water, dried over calcium chloride, filtered and the dried with anhydrous sodium sulfate and concentrated in chloroform evaporated to produce B-[l-(p-chlorobenzoyD-Z- vacuo 1 to produce B-Il-(p-chlorobenzoyl)-2-methyl-S- methyl-5-nitroindole-3] ethyl hydrogen phthalate. dimethylaminoindole-3] ethyl acetate.

In like manner, any acylated indolyl alcohol prepared in the preceding examples will form the corresponding monobasic 5 EXAMPLE 34 ester upon treatment with any other dibasic acid, for example: To 0001 mole of B4 l (p ch|mbenzy|) 2 methy| 5 B-I -(P- y y ly mitroindole-3] ethyl acetate in 30 ml. of anhydrous ethyl p py y g succinate; acetate is added 0.003 mole of acetic anhydridc. The mixture B-l (ph y y P y P Py is reduced with Raney nickel at room temperature and 40 y y l'p' y ethyl y g benloate; p.s.i. After the theoretical amount of hydrogen has been ab- B-[ l-(omethoxy-p-chlorobenzoyl)-2-(p-methoxy-phenyl)-5- sorbed, the catalyst is removed by filtration. The solution is ethylthioindole-31-heptyl hydrogen malonate; concentrated in vacuo to a small volume and poured into an ;S-[ l-(p-dimethylaminobenzoyl-Z-allyl-S-dimethylsulfamylinice water-ether mixture. The ether layer is separated and the do1 -3] thylh d e fum rate; 5 aqueous layer is washed with ether. The combined ether ex- B-[ l-(2-benzylmercaptothiazolet-carboxy )-2-phenyl-5- tracts are washed with sodium bicarbonate, followed by water,

dried with anhydrous sodium sulfate and concentrated in vacuo to dryness to produce B-[l-(p-chlorobenzoyD-Z- methyl-S-acetaminoindole-B] ethyl acetate.

b. B-[1-(p-Chlorobenzoyl)-2-methyl-5-acetaminoindole-31 cyclobutyloxyindole-3]-B-isopropylethyl hydrogen glutarate; B-[ 1-(p-formylbenzoyl)-2-ethyl-5-mercaptoindole-3 l-B- triethylmethylethyl hydrogen citraconate.

EXAMPLEGI ethyl acetate is added to a suspension of sodium hydride in dimethylformamide with stirring and ice-cooling. After 1 hour A 0f 0-025 of B-[ -(P- Y ly methyl iodide is added and the mixture is stirred overnight. 5-nitr0ind0le-31 ethyl acetate in 100 of ethanol is The reaction mixture is poured into iced-water and extracted hydrogenated in the presence of 120 mg. of a 10 percent palwith ether. Evaporation of the ethereal solution yields B-[ 1- ladium-on-charcoal catalyst, at room temperature and a pres- (p-chlorobenzoyl)-2-methyl-5-(N-methylacetamido)-indole-3 sure of 40 p.s.i. After the theoretical amount of hydrogen has yl a been consumed the hydrogenation is stopped, and the solution EXAMPLE 3 5 filtered to remove the catalyst. The filtrate is concentrated to dryness in vacuo to giveB-l1-(p-chlorobenzoyD-Z-methyl-S- Add 0.0005 mole of B-[ l-(p-chlorobenzoyl)-2-methyl-5- aminoindole-B] ethyl acetate. aminoindole-3] ethyl acetate, 1 g. of 1,4-dibromobutsne and In like manner, any other S-nitro ester prepared in ac- 0.975 g. of anhydrous sodium carbonate to 80 ml. of ethan l cordance with the procedures of this invention may be and at reflux for 5 in a Q p 1 reduced to i gj i w- L WV reaction mixture isfiltered and the filtrate concentrated l n vacuo to a small volume and diluted with ether. The solution is XA 32 washed twice with water, dried, in anhydrous I:gdium pslullfate and concentrated invacuo to dryness to p uce -(p- ..:.-.;t;?:.s:.;:.?.-f;i ".i..l.;.;;38;f;;i" i; ";;g= a e I zi fg at g g of 40 When ethylene dibromide is used instead of dibromobuto z lzvef lfe mix tu i 'e iz t lfen iluted water zn d fi i te r ed tlo g the product obtained m the 5-( l-mcydopmpyl) mdole yield B-[l-(pschlorobenzoyl)-2-methyl-5-bis(B-hydroxyethyl) e claim. amonoindole-Zl] ethyl acetate. 1. A compound of the formula b. The product of example 32a is stirred at 0 C. in pyridine with two mole proportions of p-toluenesulfonyl chloride until the reaction is substantially complete. The mixture is poured I ts into water and the S-bis (p-toluene-sulfonylethyl) amino com- I -CH -C N pound is isolated. This is dissolved in benzene and one mole proportion of methylamine is added. The mixture is allowed to stand at room temperature for 3 days. The mixture is poured into iced water containing two equivalents of sodium car- (10 bonate and extracted with ether immediately. Evaporation of the ether yields B-I l-(p-chlorobenaoyl)-2-methyl-5-(4'- methyll '-piperaginyl-indole-3] ethyl acetate.

c. A solution of p-toluenesulfonyl chloride inv 200 ml. of benzene is added dropwise with stirring to a solution of the product of Part a (0.1 mole) and pyridine (0.3 mole), in 300 ml. of benzene at room temperature over a 1 hour period. The mixture is then heated under reflux for 3 hours, washed with water and dried to produce fi-[ l-(p-chlorobenzoyD-2-methyl- 5-(4'morpholinyl)-indole-3] ethyl acetate.

in which R, is phenyl, naphthyl, biphenyl, or any of the above substituted by lower alkyl, halogen. alkoxy, phenoxy, trifluoroacetyl, nitro, phenyl, benzyl, lower alkanoyl, cyano, carboloweralkoxy, alkanoyl, trifluoromethyl, dilower alkylsulfamoyl, lower alkyl sulfinyl, lower alkyl sulfonyl, benzylthio, mercapto, diloweralkyl amine, hydroxy, lower alkylthio or benzyloxy;

EXAMPLE 33 R, is hydrogen, lower alkyl or lower alkenyl;

R is hydrogen or lower alkyl; and

To a Solution of 0-001 "1016 Of fi-l -(l yn- R is hydrogen, halogen, lower alkyl, lower alkoxy, haloaly l yl acetate in 20 of distill! kyl, nitro, lower alkenyloxy, amino, lower alkylamino, dimethoxyethane is added 1.5 ml. of glacial acetic acid and diloweralkylarnino, mercapto, lower alkyl mercapto and 0.5 ml. of 37 percent solution of aqueous formaldehyde. This benzyl mercapto. mixture is reduced with Raney nickel at 40 p.s.i. and room 2. l-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl temperature. After the theoretical amount of hydrogen has acetonitrile. reacted, the reaction mixture is filtered, concentrated in 3. l-p-chlorobenzoyl-Z-methyl-S-dimethylamino-3-indolyl vacuo to a small volume and diluted with ether. The ether acetonitrile. svlufion is hram!!!,s s ivml2iqarbpa selhsmthaatss r r s r 

2. 1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl acetonitrile.
 3. 1-p-chlorobenzoyl-2-methyl-5-dimethylamino-3-indolyl acetonitrile. 